It has been demonstrated that expression of the manganese superoxide dismutase (MnSOD) gene is essential for the survival of animals from death associated with neurodegeneration.. We propose to investigate the mechanisms by which MnSOD mediates neuroprotection. We propose to investigate the mechanisms by which MnSOD mediates neuroprotection in Alzheimer's disease (AD) using several unique animal models, as well as brains from AD patients And age-matched control subjects. The proposed experiments are aimed at providing an understanding of the manner by which MnSOD modulates neurodegeneration and how the expression of MnSOD in the brain is regulated. Aim 1 will test the hypothesis that AB brains are less efficient in removing exogenous superoxide under increased oxidative stress conditions. Superoxide removal and respiratory functions of mitochondria isolated from wild- type and knock-in mice expressing the combination of beta amyloid precursor protein (APP) and presenilin (PS-1) mutant genes will be investigated. Aim 2 will test the hypothesis that nitric oxide (NO) plays dual roles in AD-induced mitochondrial dysfunction and AD associated pathology using transgenic mice expressing the human MnSOD gene, knock-out mice lacking the inducible form of nitric oxide synthase (iNOS) gene, and crosses between the MnSOD transgenic and iNOS knock-out mice. Aim 4 will test the hypothesis Aim 4 will test the hypothesis that modulation of the oxidative stress sensitive nuclear factor kappa beta (NF-kappaB) leads to high levels expression of MnSOD and subsequent protection against Abeta-mediated brain injury. The results obtained from this study will demonstrated the cause-effect relationship between mitochondria antioxidant status and oxidative stress-mediated events in the pathophysiology of AD and will guide our future attempts to develop specific measures for prevention and treatment of AD.